Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2

ABSTRACT

This invention is directed to a compound of Formula I 
                         
or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined herein. The compounds of Formula I are useful as protein kinase (PK) inhibitors and can be used to treat such diseases as cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases inflammatory disorders and neurodegenerative disorders.

FIELD OF THE INVENTION

The invention relates to inhibitors of vascular endothelial growthfactor receptor 2 kinase (VEGFR2) or VEGFR, platelet derived growthfactor beta (PDGFR) kinases or PDGFR and Protein Kinase R (EIF2AK2), andmethods of using such compounds. The present invention is also directedto methods of regulating, modulating or inhibiting protein kinases,whether of the receptor or non-receptor class, for the prevention and/ortreatment of disorders related to unregulated protein kinase signaltransduction, including cell growth, metabolic, blood vesselproliferative, inflammatory and neurodegenerative disorders.

DESCRIPTION OF THE RELATED ART

Protein kinases (PKs) comprise a large and diverse class of proteinshaving enzymatic activity which catalyzes the transfer of the terminalphosphate of ATP to the hydroxyl group of a serine, threonine ortyrosine group in a protein. Protein kinases (PKs) are involved innumerous diseases which result from dysregulation of their normalfunction.

There are numerous examples where protein kinases, have been found to beinvolved in cellular signaling pathways leading to pathologicalconditions. In the VEGFR2 kinase protein kinase, which is a receptortyrosine kinase, pathological conditions involving aberrant angiogenesisinclude cancer, wet age-related macular degeneration (Ni et al.Opthalmologica 2009 223 401-410; Chappelow et al. Drugs 2008 681029-1036), diabetic retinopathy (Zhang et al Int. J. Biochem. CellBiol. 2009 41 2368-2371), cancer (Aora et al. J. Path. Exp. Ther. 2006,315, 971), psoriasis (Heidenreich et al Drug News Perspective 2008 2197-105) and hyper immune response. In ophthalmic diseases such asneovascular age-related macular degeneration and diabetic retinopathyaberrant activation of VEGF receptors can lead to abnormal blood vesselgrowth. The importance of VEGFR signaling in the neovascular age-relatedmacular degeneration disease process is evident by the clinical successof multiple anti-VEGF targeting agents including Lucentis®, Avastin®,and EYLEA™ (Barakat et al. Expert Opin. Investig. Drugs 2009, 18, 637).Recently it has been suggested that inhibition of multiple proteinkinase signaling pathways may provide a greater therapeutic effect thantargeting a single signaling pathway. For example in neovascular oculardisorders such as neovascular age-related macular degeneration anddiabetic retinopathy the inhibition of both VEGFR and PDGFRβ may providea greater therapeutic effect in by causing regression of existingneovascular blood vessels present in the disease (Adamis et al. Am. J.Pathol. 2006 168 2036-2053). In cancer inhibition of multiple PKsignaling pathways has been suggested to have a greater effect thaninhibiting a single PK pathway (DePinho et al. Science 2007 318 287-290;Bergers et al. J. Clin Invest. 2003 111 1287-1295).

It has also been suggested that misregulated protein kinases areinvolved in neurodegenerative disease. In particular Protein Kinase Rhas been implicated in neurodegenerative disease. Protein Kinase R (PKR,also known as interferon-induced, double-stranded RNA-activated proteinkinase, or eukaryotic translation initiation factor 2-alpha kinase 2) isone of four known mammalian kinases that phosphorylate eukaryotictranslation initiation factor 2-alpha (eIF-2α) in response to a varietyof stress conditions (Donnelly et al., Cell. Mol. Life Sci. 2013, 70,3493-3511). PKR plays a central role in the innate immune system andserves to prevent viral replication and viral infection (for a detailedreview see Garcia et al., Microbiol. and Mol. Bio. Rev. 2006, 70,1032-1060). It is proposed that in chronic conditions like AMD, innateimmune players respond to modified host derived elements (ROS/Alu) andexternal particulate matter(drusen) by activation of inflammasomecomplex. Emerging evidence indicates that PKR has a key role in NLRP3inflammasome activation (Yim & Williams; J of Interferon & Cytokine Res,2014, Campbell & Doyle, J Mol Med, 2013, Lu et. al; Nature, 2012).

The binding of double stranded RNA to the double stranded RNA regulatorydomains of PKR induces dimerization and autophosphorylation which leadsto activation of the kinase (Dever et al., Cell 2005, 122, 901-913).Once activated by dimerization PKR can suppress protein synthesis byphosphorylation of serine-51 on eukaryotic translation initiation factor2-alpha (eIF-2α). In its phosphorylated form eIF2alpha increases itsaffinity for eIF-2B by 100-fold effectively converting it into acompetitive inhibitor of eIF-2B. By this mechanism a small amount ofphosphorylated eIF2alpha can effectively inhibit the guanine nucleotideexchange activity of eIF-2B and shut down protein translation (Ramaiahet al., Biochemistry 2000, 39, 12929-12938).

In addition to PKR's role in regulation of protein synthesis it alsoplays an important role in signal transduction linked to apoptotic celldeath. PKR has been shown to be activated by dsRNA, number of growthfactors and cytokines including INF, PDGF, TNF-alpha, and IL-1 and bythe activation of Toll receptors. PKR has also been shown to bephosphorylated by JAK1 and Tyk2 kinases (Su et al., EMBO Reports 2007,3, 265). Activation of PKR leads to the activation of multiple signalingpathways that are involved in inflammation and cell death. PKR isrequired for phosphorylation of MKK6 (Williams et al., J. Biol. Chem.2004, 279, 37670-37676) and subsequent p38 MAPK signaling (Williams etal., The EMBO Journal 2000, 19, 4292-4297). PKR induces the expressionof the pro apoptotic factor CHOP and has been shown to induce apoptosisby the FADD/Caspase 8 pathway (Barber, G. et al, The EMBO Journal 1998,17, 6888-6902).

Due to its key role in regulation of apoptotic cell death PKR inhibitionmay be useful in prevention of the rod and cone photoreceptor cell deathand ganglion cell death associated with the atrophic form of maculardegeneration (Shimazawa et al, IVOS 2007, 48, 3729-3736).

The identification of effective small compounds which specificallyinhibit signal transduction by modulating the activity of receptor andnon-receptor protein kinases to regulate and modulate abnormal orinappropriate cell proliferation is therefore desirable and one objectof this invention.

SUMMARY OF THE INVENTION

The present invention relates to organic molecules capable ofmodulating, regulating and/or inhibiting protein kinase signaltransduction, useful for treating diseases related to protein kinasesignal transduction, for example, cancer, blood vessel proliferativedisorders, fibrotic disorders, and neurodegenerative diseases. Inparticular, the compounds of the present invention are useful fortreatment of mesangial cell proliferative disorders and metabolicdiseases, lung carcinomas, breast carcinomas, Non Hodgkin's lymphomas,ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma,melanoma, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,psoriasis, rosacea, diabetic mellitus, wound healing, inflammation andneurodegenerative diseases and preferably ophthalmic diseases, i.e.diabetic retinopathy, retinopathy of prematurity, macular edema, retinalvein occlusion, exudative or neovascular age-related maculardegeneration, high-risk eyes (i.e. fellow eyes have neovascularage-related macular degeneration) with dry age-related maculardegeneration, neovascular disease associated with retinal veinocclusion, neovascular disease (including choroidal neovascularization)associated with the following: pathologic myopia, pseudoxanthomaelasticum, optic nerve drusen, traumatic choroidal rupture, atrophicmacular degeneration, geographic atrophy, central serous retinopathy,cystoid macular edema, diabetic retinopathy, proliferative diabeticretinopathy, diabetic macular edema, rubeosis iridis, retinopathy ofprematurity, Central and branch retinal vein occlusions,inflammatory/infectious retinal, neovascularization/edema, cornealneovascularization, hyperemia related to an actively inflamed pterygia,recurrent pterygia following excisional surgery, post-excision,progressive pterygia approaching the visual axis, prophylactic therapyto prevent recurrent pterygia, of post-excision, progressive pterygiaapproaching the visual axis, chronic low grade hyperemia associated withpterygia, neovascular glaucoma, iris neovascularization, idiopathicetiologies, presumed ocular histoplasmosis syndrome, retinopathy ofprematurity, chronic allergic conjunctivitis, ocular rosacea,blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitissicca, ocular graft vs host disease, etc.

In one aspect, the invention provides a compound represented by FormulaI or a pharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the enantiomers, diastereoisomers, tautomers, zwitterionsand pharmaceutically acceptable salts thereof:

wherein:

X is CH or N;

R¹ is substituted or unsubstituted aromatic heterocycle, substituted orunsubstituted aryl, —OCH₃ or NHR⁸;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, substituted or unsubstituted C₁-C₈ alkyl, halogen,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,

R⁴ is hydrogen, OR⁹, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁵ is OR⁹, hydrogen, halogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁶ is OR⁹, hydrogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂ or F;

R⁷ is OR⁹, hydrogen, halogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁸ is substituted or unsubstituted heterocycle or substituted orunsubstituted aryl;

R⁹ is hydrogen or substituted or unsubstituted alkyl;

R¹⁰ is hydrogen or substituted or unsubstituted alkyl;

R¹¹ is hydrogen or substituted or unsubstituted alkyl;

R¹² is hydrogen or substituted or unsubstituted alkyl;

R¹³ is hydrogen or substituted or unsubstituted alkyl;

R¹⁴ is hydrogen or substituted or unsubstituted alkyl; and

with the proviso that the compound of Formula I is not

In another aspect, the invention provides a compound represented byFormula I wherein:

X is CH;

R¹ is substituted or unsubstituted aromatic heterocycle, substituted orunsubstituted aryl, —OCH₃ or NHR⁸;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, substituted or unsubstituted C₁-C₈ alkyl, halogen,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ or N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂

R⁴ is hydrogen, OR⁹, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁵ is OR⁹, hydrogen, halogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁶ is OR⁹, hydrogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂ or F;

R⁷ is OR⁹, hydrogen, halogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁸ is substituted or unsubstituted heterocycle or substituted orunsubstituted aryl; and

R⁹ is hydrogen or substituted or unsubstituted alkyl.

R¹⁰ is hydrogen or substituted or unsubstituted alkyl;

R¹¹ is hydrogen or substituted or unsubstituted alkyl;

R¹² is hydrogen or substituted or unsubstituted alkyl;

R¹³ is hydrogen or substituted or unsubstituted alkyl; and

R¹⁴ is hydrogen or substituted or unsubstituted alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

X is N;

R¹ is substituted or unsubstituted aromatic heterocycle, substituted orunsubstituted aryl, —OCH₃ or NHR⁸;

R² is hydrogen or substituted or unsubstituted alkyl;

R³ is hydrogen, substituted or unsubstituted C₁-C₈ alkyl, halogen,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,

O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,

R⁴ is hydrogen, OR⁹, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁵ is OR⁹, hydrogen, halogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁶ is OR⁹, hydrogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³) (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂ or F;

R⁷ is OR⁹, hydrogen, halogen, substituted or unsubstituted C₁-C₈ alkyl,(CR¹⁰R¹¹)_(a)C(O)OR¹², (CR¹⁰R¹¹)_(a)OR¹², (CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, (CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,O(CR¹⁰R¹¹)_(a)C(O)OR¹², O(CR¹⁰R¹¹)_(a)OR¹², O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹²,O(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,O(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂, O(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)C(O)OR¹², N(R¹³)(CR¹⁰R¹¹)_(a)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)R¹², N(R¹³)(CR¹⁰R¹¹)_(a)C(O) N(R¹³R¹⁴)₂,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)OR¹²,N(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³)C(O)N(R¹³R¹⁴)₂ orN(R¹³)(CR¹⁰R¹¹)_(a)N(R¹³R¹⁴)₂;

R⁸ is substituted or unsubstituted heterocycle or substituted orunsubstituted aryl;

R⁹ is hydrogen or substituted or unsubstituted alkyl;

R¹⁰ is hydrogen or substituted or unsubstituted alkyl;

R¹¹ is hydrogen or substituted or unsubstituted alkyl;

R¹² is hydrogen or substituted or unsubstituted alkyl;

R¹³ is hydrogen or substituted or unsubstituted alkyl;

R¹⁴ is hydrogen or substituted or unsubstituted alkyl; and

with the proviso that the compound of Formula I is not

In another aspect, the invention provides a compound represented byFormula I wherein:

-   -   X is CH;    -   R¹ is substituted or unsubstituted aromatic heterocycle;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen or OR⁹;    -   R⁵ is OR⁹ or hydrogen;    -   R⁶ is OR⁹, hydrogen or F;    -   R⁷ is hydrogen; and    -   R⁹ is substituted or unsubstituted alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

-   -   X is N;    -   R¹ is —OCH₃;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen or OR⁹;    -   R⁵ is OR⁹, hydrogen or halogen;    -   R⁶ is OR⁹, hydrogen or F;    -   R⁷ is hydrogen; and    -   R⁹ is substituted or unsubstituted alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

-   -   X is N;    -   R¹ is NHR⁸;    -   R² is hydrogen or substituted or unsubstituted alkyl;    -   R³ is OR⁹, hydrogen or halogen;    -   R⁴ is hydrogen or OR⁹;    -   R⁵ is OR⁹, hydrogen or halogen;    -   R⁶ is OR⁹ or hydrogen;    -   R⁷ is OR⁹, hydrogen or halogen;    -   R⁸ is substituted or unsubstituted heterocycle; and    -   R⁹ is substituted or unsubstituted alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

-   -   X is N;    -   R¹ is substituted or unsubstituted aromatic heterocycle;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen or OR⁹;    -   R⁵ is OR⁹ or hydrogen;    -   R⁶ is F, OR⁹ or hydrogen;    -   R⁷ is OR⁹, hydrogen or halogen; and    -   R⁹ is substituted or unsubstituted alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

-   -   X is N;    -   R¹ is substituted or unsubstituted aryl;    -   R² is hydrogen;    -   R³ is hydrogen;    -   R⁴ is hydrogen or OR⁹;    -   R⁵ is OR⁹ or hydrogen;    -   R⁶ is F, OR⁹ or hydrogen;    -   R⁷ is OR⁹, hydrogen or halogen; and    -   R⁹ is substituted or unsubstituted alkyl;

with the proviso that the compound of Formula I is not

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 12 carbon atoms. One methylene(—CH₂—) group, of the alkyl group can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate,amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl, by a divalentheterocycle, or by a divalent aryl group. Alkyl groups can have one ormore chiral centers. Alkyl groups can be independently substituted byhalogen atoms, hydroxyl groups, cycloalkyl groups, amino groups,heterocyclic groups, aryl groups, carboxylic acid groups, phosphonicacid groups, sulphonic acid groups, phosphoric acid groups, nitrogroups, amide groups, sulfonamide groups, ester groups, ketone groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen atoms, sulfonylC₁₋₈ alkyl groups, sulfoxide C₁₋₈ alkyl groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₈ alkyl groups,—C₁₋₈ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketonegroups, alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkylgroups or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having at least one double bond. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be independentlysubstituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitrogroups, cyano groups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₆alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups,alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups orhydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group, ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₆ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon moiety having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected form oxygen, nitrogen,sulfur, or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₈ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms, by removal of one hydrogen atom. Aryl can be substituted byhalogen atoms, sulfonyl C₁₋₆ alkyl groups, sulfoxide C₁₋₆ alkyl groups,sulfonamide groups, carboxcyclic acid groups, C₁₋₆ alkyl carboxylates(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₆ alkylgroups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups,—C₂₋₆ alkynyl groups, ketone groups, aldehydes, alkylamino groups, aminogroups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxyl groups. Arylscan be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —C(O)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “ester” as used herein, represents an organic compound having acarbonyl group linked to a carbon atom such as —C(O)OR^(x) wherein R^(x)can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as definedabove.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂⁻”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Other defined terms are used throughout this specification:

“DMF” refers to dimethylformamide

“PDGFRβ” refers to platelet derived growth factor receptor beta

“PKs” refers to protein kinase

“PKR” refers to Protein Kinase R

“RTKs” refers to receptor tyrosine kinase

“VEGF” refers to vascular endothelial growth factor

“VEGFR” refers to vascular endothelial growth factor receptor

Compounds of the invention are:

-   6-(pyridin-3-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-phenyl-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-phenyl-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   2-anilino-N-pyridin-3-yl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide;-   6-benzoyl-N-[5-(ethylsulfonyl)-2-methoxyphenyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   6-benzoyl-N-[5-(ethylsulfonyl)-2-methoxyphenyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-(4-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-(3-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-(2-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-(1-methyl-1H-pyrazol-5-yl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   2-(pyridin-3-ylcarbonyl)-N-3-thienyl-1,2,3,4-tetrahydroisoquinolin-6-amine;-   N-(3-fluorophenyl)-2-(pyridin-3-ylcarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-amine;-   6-(3-methyl-2-furoyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   6-[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   6-(2-thienylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   6-isonicotinoyl-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   6-(pyridin-2-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-(3,4-dimethoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   N-(3,5-dimethoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   methyl    2-[(3,4,5-trimethoxyphenyl)amino]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate;-   2-[(3,4,5-trimethoxyphenyl)amino]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide;-   7-(pyridin-3-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-amine.

Compounds of formula I are useful as protein kinase inhibitors. As such,compounds of formula I will be useful for treating diseases related tounregulated protein kinase signal transduction, for example, cancer,blood vessel proliferative disorders, fibrotic disorders, inflammatorydisorders and neurodegenerative diseases. In particular, the compoundsof the present invention are useful for treatment of mesangial cellproliferative disorders and metabolic diseases, lung carcinomas, breastcarcinomas, Non Hodgkin's lymphomas, ovarian carcinoma, pancreaticcancer, malignant pleural mesothelioma, melanoma, arthritis, restenosis,hepatic cirrhosis, atherosclerosis, psoriasis, rosacea, diabeticmellitus, wound healing, inflammation and neurodegenerative diseases andpreferably ophthalmic diseases, i.e. diabetic retinopathy, retinopathyof prematurity, macular edema, retinal vein occlusion, exudative orneovascular age-related macular degeneration, high-risk eyes (i.e.fellow eyes have neovascular age-related macular degeneration) with dryage-related macular degeneration, neovascular disease associated withretinal vein occlusion, neovascular disease (including choroidalneovascularization) associated with the following: pathologic myopia,pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidalrupture, atrophic macular degeneration, geographic atrophy, centralserous retinopathy, cystoid macular edema, diabetic retinopathy,proliferative diabetic retinopathy, diabetic macular edema, rubeosisiridis, retinopathy of prematurity, Central and branch retinal veinocclusions, inflammatory/infectious retinal, neovascularization/edema,corneal neovascularization, hyperemia related to an actively inflamedpterygia, recurrent pterygia following excisional surgery,post-excision, progressive pterygia approaching the visual axis,prophylactic therapy to prevent recurrent pterygia, of post-excision,progressive pterygia approaching the visual axis, chronic low gradehyperemia associated with pterygia, neovascular glaucoma, irisneovascularization, idiopathic etiologies, presumed ocularhistoplasmosis syndrome, retinopathy of prematurity, chronic allergicconjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrentepiscleritis, keratoconjunctivitis sicca, ocular graft vs host disease,etc.

Some compounds of Formula I and some of their intermediates have atleast one asymmetric center in their structure. This asymmetric centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic acid,hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonicacid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinicacid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonicacid, formic and the like (Handbook of Pharmaceutical Salts, P. HeinrichStahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich,2002, 329-345). The base addition salt form of a compound of Formula Ithat occurs in its acid form can be obtained by treating the acid withan appropriate base such as an inorganic base, for example, sodiumhydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide,ammonia and the like; or an organic base such as for example,L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.(Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G.Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Pharmaceutical compositions containing invention compounds may be in aform suitable for topical use, for example, as oily suspensions, assolutions or suspensions in aqueous liquids or nonaqueous liquids, or asoil-in-water or water-in-oil liquid emulsions. Pharmaceuticalcompositions may be prepared by combining a therapeutically effectiveamount of at least one compound according to the present invention, or apharmaceutically acceptable salt thereof, as an active ingredient withconventional ophthalmically acceptable pharmaceutical excipients and bypreparation of unit dosage suitable for topical ocular use.

The therapeutically efficient amount typically is between about 0.0001and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquidformulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventionalpharmaceutically acceptable preservatives, stabilizers and surfactants.Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar manner an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene. Other excipient componentswhich may be included in the ophthalmic preparations are chelatingagents. The preferred chelating agent is edentate disodium, althoughother chelating agents may also be used in place of or in conjunctionwith it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.8 antioxidant as needed surfactant as needed purifiedwater to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses. Especially preservative-free solutions are oftenformulated in non-resealable containers containing up to about ten,preferably up to about five units doses, where a typical unit dose isfrom one to about 8 drops, preferably one to about 3 drops. The volumeof one drop usually is about 20-35 μl.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner. The present invention isfurther directed to pharmaceutical compositions comprising apharmaceutically effective amount of one or more of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient,wherein said compositions are effective for treating the above diseasesand conditions; especially ophthalmic diseases and conditions. Such acomposition is believed to modulate signal transduction by a proteinkinase, either by inhibition of catalytic activity, affinity to ATP orability to interact with a substrate.

More particularly, the compositions of the present invention may beincluded in methods for treating diseases comprising proliferation,fibrotic or metabolic disorders, for example cancer, fibrosis,psoriasis, rosacea, atherosclerosis, arthritis, and other disordersrelated to abnormal vasculogenesis and/or angiogenesis, such asexudative age related macular degeneration and diabetic retinopathy.

The present invention is further directed to pharmaceutical compositionscomprising a pharmaceutically effective amount of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient. Such acomposition is believed to modulate signal transduction by a proteinkinase, tyrosine kinase, or serine threonine kinase either by inhibitionof catalytic activity, affinity to ATP or ability to interact with asubstrate.

The present invention relates to compounds capable of regulating and/ormodulating protein kinase signal transduction and more particularlyreceptor and non-receptor protein kinase signal transduction.

Receptor tyrosine kinase mediated signal transduction is initiated byextracellular interaction with a specific growth factor (ligand),followed by receptor dimerization, transient stimulation of theintrinsic protein tyrosine kinase activity and phosphorylation. Bindingsites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic effects and responses to theextracellular microenvironment).

It has been shown that tyrosine phosphorylation sites in growth factorreceptors function as high-affinity binding sites for SH2 (src homology)domains of signaling molecules. Several intracellular substrate proteinsthat associate with receptor tyrosine kinases have been identified. Theymay be divided into two principal groups: (1) substrates which have acatalytic domain; and (2) substrates which lack such domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors and SH2 domains oftheir substrates is determined by the amino acid residues immediatelysurrounding the phosphorylated tyrosine residue.

Differences in the binding affinities between SH2 domains and the aminoacid sequences surrounding the phosphotyrosine residues on particularreceptors are consistent with the observed differences in theirsubstrate phosphorylation profiles. These observations suggest that thefunction of each receptor tyrosine kinase is determined not only by itspattern of expression and ligand availability but also by the array ofdownstream signal transduction pathways that are activated by aparticular receptor. Thus, phosphorylation provides an importantregulatory step which determines the selectivity of signaling pathwaysrecruited by specific growth factor receptors, as well asdifferentiation factor receptors.

Protein kinase signal transduction results in, among other responses,cell proliferation, differentiation and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis,arthritis and diabetic retinopathy (or other disorders related touncontrolled angiogenesis and/or vasculogenesis, e.g. maculardegeneration).

This invention is therefore directed to compounds which regulate,modulate and/or inhibit protein kinase signal transduction by affectingthe enzymatic activity of the PKs and interfering with the signaltransduced by such proteins. More particularly, the present invention isdirected to compounds which regulate, modulate and/or inhibit theproteinkinase mediated signal transduction pathways as a therapeuticapproach to cure many kinds of solid tumors, including but not limitedto carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma,meningioma, astrocytoma, melanoma and myoblastoma. Indications mayinclude, but are not limited to brain cancers, bladder cancers, ovariancancers, gastric cancers, pancreas cancers, colon cancers, bloodcancers, lung cancers and bone cancers.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic Schemes set forth below, illustrate how thecompounds according to the invention can be made.

At this stage, those skilled in the art will appreciate that manyadditional compounds that fall under the scope of the invention may beprepared by performing various common chemical reactions. Details ofcertain specific chemical transformations are provided in the examples.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I. The present invention is not to be limited inscope by the exemplified embodiments which are intended as illustrationsof single aspects of the invention only. Indeed, various modificationsof the invention in addition to those described herein will becomeapparent to those skilled in the art from the foregoing description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of regulating, modulating orinhibiting proteinkinases, whether of the receptor or non-receptorclass, for the prevention and/or treatment of disorders related tounregulated protein kinase signal transduction, including cell growth,metabolic, and blood vessel proliferative disorders, which comprisesadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of at least one kinase inhibitor as described herein.

In another aspect, the invention provides the use of at least one kinaseinhibitor for the manufacture of a medicament for the treatment of adisease or a condition mediated by tyrosine kinases in a mammal.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACDLabs version 12.5. Some of theintermediate and reagent names used in the examples were generated withsoftware such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 fromMDL ISIS Draw 2.5 SP1.

In general, characterization of the compounds is performed according tothe following methods; NMR spectra are recorded on 300 or 600 MHz Varianand acquired at room temperature. Chemical shifts are given in ppmreferenced either to internal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by medium pressureliquid chromatography, unless noted otherwise.

N-(3,4,5-Trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A mixture oftert-Butyl-2-[(3,4,5-trimethoxyphenyl)amino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carboxylate,Intermediate 2 (870 mg, 2.09 mmol) in 4.0 N HCl solution in 1,4-dioxane(15 mL) was stirred at room temperature for 20 hours (orange coloredsolution with precipitate). The solvent was removed in vacuo and thesalt was mostly taken up in water (20 mL). The pH of the aqueous mixturewas made basic by addition of 1.0 N NaOH_((aq)) and the white, amorphousprecipitate was collected, washed with water, ethyl acetate, and dried(616 mg, 93%).

t-Butyl-2-[(3,4,5-trimethoxyphenyl)amino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6-carboxylate

A mixture of6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine,Intermediate 3 (500 mg, 2.0 mmol), 5-bromo-1,2,3-trimethoxybenzene (494mg, 2.0 mmol), Cl-BrettPhos-Pd precatalyst/BrettPhos admixture (53 mg,0.040 mmol (1:1 mol: mol)) and cesium carbonate (912 mg, 2.80 mmol) int-BuOH (15 mL) was heated at 110° C. for 16 hours. Upon cooling, thereaction mixture was diluted with EtOAc and the insolubles were filteredoff (celite). The filtrate was concentrated and the residue was elutedthrough a flash column (silica gel 60, 230-400 mesh, 2:3 hexanes:EtOAc)to obtain a clear glass (659 mg, 79%).

6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine

A solution of1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone, Intermediate4 (7.64 g, 30.04 mmol) in methanol (190 mL) was treated with guanidinecarbonate (21.65 g, 120.16 mmol), followed by sodium acetate trihydrate(32.70 g, 240.32 mmol). The reaction mixture was heated at reflux for 17hours and the solvent was removed in vacuo. The residue was diluted withwater and the mixture was swirled for a few minutes. The undissolvedwhite solid was collected and washed with water, followed by a smallamount of cold ethyl acetate to give the title compound (4.10 g, 55%).

1-t-Butoxycarbonyl-3-(dimethylamino)methylene-4-piperidone

A solution of N-t-Butoxycarbonyl-4-piperidone (10.0 g, 50.19 mmol) andN,N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in1,4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent wasremoved in vacuo and the residue was eluted through a flash column(silica gel 60, 230-400 mesh, 8% MeOH in EtOAc) to obtain the titlecompound as an orange oil which crystallized on standing (7.64 g, 60%).

(2-Chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone

A solution of nicotinoyl chloride (0.230 g, 1.62 mmol) in anhydrous THF(1.5 mL) was treated with2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.250 g, 1.47 mmol)and triethylamine (0.3 g, 3.0 mmol) and subsequently allowed to stir atroom temperature. After 4 hours the reaction was quenched with deionizedH₂O (10 mL). Following dilution with EtOAc (10 mL) the reaction mixturewas washed twice with brine and once with saturated Na₂HCO_(3(aq)). Thecombined aqueous layers were then washed once with EtOAc. The combinedorganic layers were dried over anhydrous Na₂SO_(4(s)), filtered and thenconcentrated in vacuo. Purification over silica using a Methanol/CHCl₃gradient afforded the desired product in 87.9% yield (0.356 g, 1.3mmol).

¹H NMR (600 MHz, DMSO-d6) δ ppm 3.18 (m, 1H) 3.25 (m, 1H) 3.92 (m, 1H)4.42 (m, 1H) 4.55 (m, 1H) 7.47 (dd, J=7.92, 4.68 Hz, 1H) 7.86 (d, J=7.92Hz, 1H) 8.34 (s, 1H) 8.65 (d, J=4.68 Hz, 1H) 8.70 (s, 1H)

N-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of t-butyl2-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate,Intermediate 7 (2.51 g, 7.69 mmol) in acetone (20 mL) was treated with5-6 N HCl solution in i-PrOH (6 mL) and the reaction mixture was stirredat room temperature for 27 hours. The solvent was removed in vacuo andthe salt was dissolved in water. The aqueous layer was washed with EtOAcand basified with 1.0 N NaOH_((aq)). The alkaline mixture was extractedwith CH₂Cl₂ (2×100 mL) and the combined CH₂Cl₂ extracts were dried(MgSO₄), filtered, and concentrated to a yellow, crystalline solid (1.25g, 72%).

t-Butyl 2-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

A mixture of6-t-Butoxycarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ylamine,Intermediate 3 (996 mg, 3.98 mmol), bromobenzene (0.42 mL, 3.98 mmol),Cl-BrettPhos-Pd/BrettPhos 1 mol/1 mol admixture (133 mg, 0.0995 mmol)and cesium carbonate (1.82 g, 5.57 mmol) in t-BuOH (30 mL) was heated at100° C. for 16 hours. Upon cooling to ambient temperature, the reactionmixture was diluted with CH₂Cl₂ and the insolubles were filtered off(celite). The filtrate was concentrated and the residue was elutedthrough a flash column (silica gel 60, 230-400 mesh, 7:3 hexanes:EtOAc)to obtain a yellow glass (770 mg, 59%).

(6-Chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-3-yl)methanone

A solution of nicotinoyl chloride (0.084 g, 0.593 mmol) in anhydrous THF(1.2 mL) was treated with 6-chloro-1,2,3,4-tetrahydro-2,7-naphthyridine(0.100 g, 0.593 mmol) and triethylamine (0.12 mL, 1.19 mmol). andsubsequently allowed to stir at room temperature. After 4 hours thereaction was quenched with deionized H₂O (10 mL). Following dilutionwith EtOAc (10 mL) the reaction mixture was washed twice with brine andonce with saturated Na₂HCO_(3(aq)). The combined aqueous layers werethen washed once with EtOAc. The organic layers were combined, driedover anhydrous Na₂SO_(4(s)), filtered and then concentrated in vacuo.Purification over silica using a Methanol/CHCl₃ gradient afforded thedesired product, in 73.3% yield (0.119356 g, 0.435 mmol).

6-(Pyridin-3-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution ofN-(3,4,5-Trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (75 mg, 0.24 mmol) in CH₂Cl₂ (1.5 mL) was cooled to 0° C.and treated with benzoic anhydride (56.7 mg, 0.251 mmol) and pyridine(22 microliter, 0.273 mmol). After 1 hour the reaction mixture wasdiluted with CH₂Cl₂ and washed with water. The organic phase wascollected, dried and concentrated. The residue was purified by silicagel chromatography (15-40% acetone/CH₂Cl₂). The product containingfractions were concentrated to give the title compound (75 mg).

N-phenyl-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 3,4,5-trimethoxyaniline (0.021 g, 0.0498 mmol). The resultingmixture was heated to 60° C. and allowed to stir overnight. After beingallowed to cool to room temperature EtOAc (10 mL) was added to thereaction mixture, and the resulting solution was then washed twice withbrine (10 mL). The combined aqueous layers were washed once with EtOAc(10 mL). The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 54.8% yield (0.021 g, 0.049 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.78-2.97 (m, 2H) 3.52-3.60 (m, 1H) 3.61(s, 3H) 3.75 (s, 6H) 3.96 (m, 1H) 4.33 (br s., 1H) 4.76 (br s, 1H)7.21-7.30 (m, 2H) 7.41-7.52 (m, 1H) 7.79-7.88 (m, 1H) 8.41 (s, 0.61 H,major rotamer) 8.66-8.70 (m, 2H) 9.41 (br. s., 1H).

2-anilino-N-pyridin-3-yl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide

A solution of N-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 6 (75 mg, 0.33 mmol), 3-isocyanatopyridine (41.8 mg, 0.35mmol) in CH₂Cl₂ (1.5 mL) was stirred at room temperature for 1 hour.After 1 hour the reaction mixture was diluted with CH₂Cl₂ and washedwith sat. aqueous NaHCO_(3(aq)). The organic phase was collected, driedand concentrated. The residue was dissolved in CH₂Cl₂ and washed with 3%aqueous LiCl solution and water. The organic phase was collected, driedand concentrated to give the title compound (45.9 mg).

6-benzoyl-N-[5-(ethylsulfonyl)-2-methoxyphenyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of N-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 5 (75 mg, 0.33 mmol) in a solution of triethylamine (0.1mL, 0.76 mmol) and CH₂Cl₂ (1.5 mL) was treated with nicotinoylhydrochloride (62 mg, 0.348 mmol). The reaction mixture was stirred forovernight. The reaction mixture was treated with additionaltriethylamine (0.05 mL, 0.38 mmol), nicotinoyl hydrochloride (31 mg,0.18 mmol) and DMF (1.5 mL) and stirring was continued at roomtemperature. The reaction was then washed with saturated aqueousNaHCO_(3(aq)) and the organic phase collected, dried and concentrated invacuo. The residue was purified by silica gel chromatography (EtOAc,hexane). The product containing fractions were collected, dried andconcentrated to give the title compound (38.7 mg).

N-(4-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 4-methoxyaniline (0.018 g, 0.100 mmol). The resulting mixture washeated to 60° C. and allowed to stir overnight. After being allowed tocool to room temperature EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 24.3% yield (0.008 g, 0.024 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.81-2.94 (m, 2H) 3.53-3.62 (m, 4H) 3.99(m, 1H) 4.43 (br. s., 1H) 4.72 (br s, 1H) 7.16-7.25 (m, 2H) 7.51-7.61(m, 1H) 7.84-7.98 (m, 2H) 8.42 (s, 0.71H, major rotamer) 8.66-8.70 (m,2H) 9.44 (br. s., 1H).

N-(3-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 3-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture washeated to 60° C. and allowed to stir overnight. After being allowed tocool to room temperature EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 51.7% yield (0.017 g, 0.047 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.77-2.95 (m, 2H) 3.49-3.56 (m, 1H) 3.73(s, 3H) 3.95 (m, 1H) 4.33 (br. s., 1H) 4.69 (br s, 1H) 6.73 (m, 1H)7.16-7.20 (m, 3H) 7.17-7.27 (m, 2H) 7.4-7.5 (m, 1H) 7.8-7.9 (m, 1H) 8.39(s, 0.59H, major rotamer) 8.68-8.71 (m, 2H) 9.50 (br. s., 1H).

N-(2-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 2-methoxyaniline (0.012 g, 0.100 mmol). The resulting mixture washeated to 60° C. and allowed to stir overnight. After being allowed tocool to room temperature EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 33.5% yield (0.011 g, 0.030 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.73-2.95 (m, 2H) 3.55-3.58 (m, 1H) 3.82(s, 3H) 3.91 (m, 1H) 4.53 (br. s., 1H) 4.75 (br s, 1H) 6.78-6.79 (m, 1H)7.10-7.22 (m, 1H) 7.35-7.46 (m, 1H) 7.77-8.02 (m, 2H) 8.46 (s, 0.60H,major rotamer) 8.69-8.75 (m, 2H) 9.21 (br. s., 1H).

N-(1-methyl-1H-pyrazol-5-yl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 1-methyl-1H-pyrazol-5-amine (0.010 g, 0.100 mmol). The resultingmixture was heated to 60° C. and allowed to stir overnight. After beingallowed to cool to room temperature EtOAc (10 mL) was added to thereaction mixture, and the resulting solution was then washed twice withbrine (10 mL). The combined aqueous layers were washed once with EtOAc(10 mL). The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 62.3% yield (0.019 g, 0.057 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.59-2.72 (m, 2H) 3.52-3.59 (m, 1H) 3.61(s, 3H) 3.95 (m, 1H) 4.53 (br. s., 1H) 4.71 (br s, 1H) 6.10 (s, 1H) 7.22(s, 1H) 7.4-7.5 (m, 1H) 7.81-7.90 (m, 1H) 8.41 (s, 0.66H, major rotamer)8.68-8.73 (m, 2H) 9.24 (br. s., 1H).

2-(pyridin-3-ylcarbonyl)-N-3-thienyl-1,2,3,4-tetrahydroisoquinolin-6-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith thiophen-3-amine (0.0099 g, 0.100 mmol). The resulting mixture washeated to 60° C. and allowed to stir overnight. After being allowed tocool to room temperature EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 39.1% yield (0.012 g, 0.035 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.69-2.84 (m, 2H) 3.51-3.55 (m, 1H) 3.88(m Hz, 1H) 4.44 (br. s., 1H) 4.75 (br s, 1H) 6.89-6.91 (m 2H) 7.00 (d,J=5.6, Hz, 1H) 7.29-7.38 (m, 1H) 7.81-7.92 (m, 1H) 8.38 (s, 0.64H, majorrotamer) 8.68-8.72 (m, 2H) 9.38 (br. s., 1H).

N-(3-fluorophenyl)-2-(pyridin-3-ylcarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 3-fluoroaniline (0.011 g, 0.100 mmol). The resulting mixture washeated to 60° C. and allowed to stir overnight. After being allowed tocool to room temperature EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 75.5% yield (0.024 g, 0.069 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.74-2.93 (m, 2H) 3.50-3.58 (m, 1H) 3.71(s, 3H) 3.93 (m, 1H) 4.49 (br. s., 1H) 4.61 (br s, 1H) 6.65 (m, 1H)7.23-7.40 (m, 3H) 7.15-7.25 (m, 2H) 7.41-7.52 (m, 1H) 7.83-7.92 (m, 1H)8.39 (s, 0.75H, major rotamer) 8.49-8.55 (m, 2H) 9.42 (br. s., 1H).

6-(3-methyl-2-furoyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium-hexafluorophosphate(0.035 g, 0.079 mmol) in anhydrous DMF (2 mL) was treated sequentiallywith 3-methylfuran-2-carboxylic acid (0.013 g, 0.103 mmol) anddiisopropylethylamine (0.035 mL, 0.159 mmol). The reaction mixture wasallowed to stir for 30 minutes at room temperature. After 30 minutes,N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (0.025 g, 0.079 mmol) was added to the reaction mixture.The reaction was allowed to stir for 3 hours at room temperature. Thereaction mixture was then diluted with EtOAc and washed three times withbrine. The combined aqueous layers were then washed twice with EtOAc.The organic layers were combined, dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude product was then purifiedover silica using a MeOH/CHCl₃ gradient affording the final product in47.3% yield (0.014 g, 0.037 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.00 (s, 3H) 2.75-2.94 (m, 2H) 3.51-3.58(m, 1H) 3.58 (s, 3H) 3.69 (s, 6H) 3.92 (m, 1H) 4.43 (br. s., 1H) 4.61(br s, 1H) 6.38 (bs, 1H) 7.15-7.24 (m, 2H) 7.28 (bs, 1H) 8.39 (s, 0.79H,major rotamer) 9.41 (br. s., 1H).

6-[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (0.035 g, 0.079 mmol) in anhydrous DMF (2 mL) wastreated sequentially with 1,3-dimethyl-1H-pyrazole-5-carboxylic acid(0.014 g, 0.103 mmol) and diisopropylethylamine (0.035 mL, 0.159 mmol).The reaction mixture was allowed to stir for 30 minutes at roomtemperature. After 30 minutes,N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (0.025 g, 0.079 mmol) was added to the reaction mixture.The reaction was allowed to stir for 3 hours at room temperature. Thereaction mixture was then diluted with EtOAc and washed three times withbrine. The combined aqueous layers were then washed twice with EtOAc.The organic layers were combined, dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude product was then purifiedover silica using a MeOH/CHCl₃ gradient affording the final product in52% yield (0.018 g, 0.041 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.22 (s, 3H) 2.76-2.95 (m, 2H) 3.52-3.59(m, 1H) 3.61 (s, 3H) 3.74 (s, 6H) 3.95 (m, 1H) 4.10 (s, 3H) 4.43 (br.s., 1H) 4.71 (br s, 1H) 6.66 (bs, 1H) 7.17-7.27 (m, 2H) 8.42 (s, 0.63H,major rotamer) 9.44 (br. s., 1H).

6-(2-thienylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (0.021 g, 0.047 mmol) in anhydrous DMF (1.5 mL) wastreated sequentially with thiophene-2-carboxylic acid (0.008 g, 0.062mmol) and diisopropylethylamine (0.025 mL, 0.095 mmol). The reactionmixture was allowed to stir for 30 minutes at room temperature. After 30minutes,N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (0.015 g, 0.047 mmol) was added to the reaction mixture.The reaction was allowed to stir for 3 hours at room temperature. Thereaction mixture was then diluted with EtOAc and washed three times withbrine. The combined aqueous layers were then washed twice with EtOAc.The organic layers were combined, dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude product was then purifiedover silica using a MeOH/CHCl₃ gradient affording the final product in40% yield (0.008 g, 0.019 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.66-2.91 (m, 2H) 3.48-3.55 (m, 1H) 3.49(s, 3H) 3.59 (s, 6H) 3.97 (m, 1H) 4.37 (br. s., 1H) 4.56 (br s, 1H)7.27-7.37 (m, 3H) 7.37-7.45 (m, 1H) 7.61-7.77 (m, 1H) 8.44 (s, 0.65H,major rotamer) 9.24 (br. s., 1H).

6-isonicotinoyl-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

To a mixture ofN-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (94.8 mg, 0.30 mmol) and isonicotinoyl chloridehydrochloride (56.1 mg, 0.32 mmol) in THF (2.0 mL) at room temperaturewas added N,N-diisopropylethylamine (0.157 mL, 0.90 mmol). Afterstirring for 3 hours at room temperature, an additional 21 mg ofisonicotinoyl chloride hydrochloride was added and the reactioncontinued for 17 hours. The reaction was quenched with H₂O, then treatedwith an EtOAc/saturated NaHCO_(3(aq)) solution work-up to give anoff-white solid. The solid was recrystallized from EtOAc/hexane toafford a white solid (115 mg, 91%).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.76-2.95 (m, 2H) 3.52-3.59 (m, 1H) 3.61(s, 3H) 3.74 (s, 6H) 3.95 (t, J=6.74 Hz, 1H) 4.43 (br. s., 1H) 4.71 (s,1H) 7.17-7.27 (m, 2H) 7.39-7.56 (m, 2H) 8.19 (s, 0.37H, minor rotamer)8.42 (s, 0.63H, major rotamer) 8.67-8.74 (m, 2H) 9.44 (br. s., 1H).

6-(pyridin-2-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A mixture of 2-picolinic acid (40.6 mg, 0.33 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (125 mg, 0.33mmol) in DMF (2.0 mL) was stirred at room temperature for 5 minutes,thenN-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (94.8 mg, 0.30 mmol; see Syntheses of Starting Materialssection for prep) added and the reaction continued for 1.5 hours at rt.The reaction mixture was treated with an EtOAc/aqueous Na₂CO_(3(aq))solution work-up to give an orange oil. The oil was chromatographedeluting with 5% MeOH in 1:1 EtOAc/CHCl₃ giving an off-white solid (107mg, 85%).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.84-2.93 (m, 2H) 3.61 (s, 3H) 3.68-3.73(m, 1H) 3.74 (s, 6H) 3.97 (t, J=5.86 Hz, 1H) 4.58 (s, 1H) 4.74 (s, 1H)7.19-7.26 (m, 2H) 7.49-7.56 (m, 1H) 7.59-7.69 (m, 1H) 7.92-8.00 (m, 1H)8.18 (s, 0.40H, minor rotamer) 8.42 (s, 0.60H, major rotamer) 8.63 (d,J=4.69 Hz, 1H) 9.38-9.45 (m, 1H).

N-(3,4-dimethoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 3,4-dimethoxyaniline (0.015 g, 0.100 mmol). The resulting mixturewas heated to 60° C. and allowed to stir overnight. After being allowedto cool to room temperature, EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 53% yield (0.019 g, 0.049 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.71-2.91 (m, 2H) 3.42-3.49 (m, 1H) 3.71(s, 3H) 3.84 (s, 3H) 3.95 (m, 1H) 4.33 (br. s., 1H) 4.71 (br s, 1H) 6.82(d, J=8.1, 1 H) 7.23 (d, J=8.1, 1H) 7.34-7.45 (m, 1H) 7.60 (s, 1H)7.81-7.92 (m, 1H) 8.42 (s, 0.66H, major rotamer) 8.86-8.90 (m, 2H) 9.64(br. s., 1H).

N-(3,5-dimethoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine

A solution of(2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone,Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treatedwith 3,4-dimethoxyaniline (0.015 g, 0.100 mmol). The resulting mixturewas heated to 60° C. and allowed to stir overnight. After being allowedto cool to room temperature, EtOAc (10 mL) was added to the reactionmixture, and the resulting solution was then washed twice with brine (10mL). The combined aqueous layers were washed once with EtOAc (10 mL).The organic layers were combined, then dried over anhydrousNa₂SO_(4(s)), filtered and concentrated in vacuo. The resulting cruderesidue was then purified over silica using a MeOH/CHCl₃ gradient. Thedesired product was obtained in 62% yield (0.022 g, 0.056 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.72-2.91 (m, 2H) 3.50-3.54 (m, 1H) 3.71(s, 6H) 3.93 (m, 1H) 4.53 (br. s., 1H) 4.72 (br s, 1H) 7.17-7.29 (m, 2H)7.48-7.54 (m, 1H) 7.62 (s, 1H) 7.89-7.99 (m, 1H) 8.48 (s, 0.67H, majorrotamer) 8.67-8.75 (m, 2H) 9.55 (br. s., 1H).

Methyl2-[(3,4,5-trimethoxyphenyl)amino]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

A solution ofN-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine,Intermediate 1 (0.020 g, 0.063 mmol) in anhydrous THF (2.0 mL) wastreated sequentially with dimethyl carbonate (0.006 g, 0.063 mmol) anddiisopropylethylamine (0.025 mL, 0.095 mmol). The reaction was heated to60° C. and allowed to stir for 5 hours. The reaction was cooled to roomtemperature, then diluted with EtOAc and washed three times with brine.The combined aqueous layers were then washed twice with EtOAc. Theorganic layers were combined, dried over anhydrous Na₂SO_(4(s)),filtered and concentrated in vacuo. The crude product was then purifiedover silica using a EtOAc/Hexanes gradient affording the final productin 64% yield (0.015 g, 0.040 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.56-2.65 (m, 2H) 3.42-3.49 (m, 1H) 3.51(s, 3H) 3.64 (s, 6H) 3.85 (m, 1H) 4.35 (br. s., 1H) 4.62 (br s, 1H)7.07-7.18 (m, 2H) 7.37-7.46 (m, 1H) 7.71-7.81 (m, 1H) 8.32 (s, 0.80H,major rotamer) 8.57-8.69 (m, 2H) 9.56 (br. s., 1H).

2-[(3,4,5-Trimethoxyphenyl)amino]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

Under anhydrous conditions(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-3-yl)methanone,Intermediate 8 (0.025 g, 0.091 mmol), Cs₂CO_(3(s)) (0.060 g, 0.183 mmol)and 3,4,5-trimethoxyaniline (0.018 g, 0.100 mmol) were added to toluene(1 mL) that had been degassed with N_(2(g)). To that mixture was addedPd(OAc)₂ (0.002 g, 0.009 mmol) then2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.028 g, 0.046 mmol) andthe reaction mixture was allowed to stir for 4 h at room temperature.Subsequently the reaction mixture was diluted with EtOAc and washed withH₂O twice. The combined aqueous layers were then washed with EtOAc. Theorganic layers were combined, dried over anhydrous Na₂SO_(4(s)),filtered and then concentrated in vacuo. The crude residue was purifiedover silica using a MeOH/CHCl₃ gradient affording the final product in31% yield (0.012 g, 0.028 mmol).

¹H NMR (300 MHz, DMSO-d6) δ ppm 2.79-2.93 (m, 2H) 3.73 (s, 6H) 3.81 (s,3H) 3.92-4.09 (m, 2H) 4.57 (br s, 1H) 4.64 (br s, 1H) 6.53 (br s, 2H)6.74 (s, 1H) 7.44-7.48 (m, 1H) 7.93 (d, J=7.92 Hz, 1H) 8.10 (br s, 0.9H,major rotamer) 8.70-8.82 (m, 2H) 9.37 (br. s., 1H).

Biological data for the compounds of the present invention was generatedby use of the following assays.

VEGFR2 Kinase Assay

Biochemical KDR kinase assays were performed in 96 well microtiterplates that were coated overnight with 75 μg/well of poly-Glu-Tyr (4:1)in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates werewashed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked byincubation with PBS containing 1% BSA, then washed with 2 mls per wellPBS-T prior to starting the reaction. Reactions were carried out in 100μL reaction volumes containing 2.7 μM ATP in kinase buffer (50 mM Hepesbuffer pH 7.4, 20 mM MgCl₂, 0.1 mM MnCl₂ and 0.2 mM Na₃VO₄). Testcompounds were reconstituted in 100% DMSO and added to the reaction togive a final DMSO concentration of 5%. Reactions were initiated by theaddition 20 ul per well of kinase buffer containing 200-300 ng purifiedcytoplasmic domain KDR protein (BPS Bioscience, San Diego, Calif.).Following a 15 minute incubation at 30° C., the reactions were washed 2mls per well PBS-T. 100 μl of a monoclonal anti-phosphotyrosineantibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added to thewells for 30 minutes. Following a 2 mls per well wash with PBS-Tween-20,100 μl of 0-Phenylenediamine Dihydrochloride in phosphate-citratebuffer, containing urea hydrogen peroxide, was added to the wells for7-10 minutes as a colorimetric substrate for the peroxidase. Thereaction was terminated by the addition of 100 μl of 2.5N H₂SO₄ to eachwell and read using a microplate ELISA reader set at 492 nm. IC₅₀ valuesfor compound inhibition were calculated directly from graphs of opticaldensity (arbitrary units) versus compound concentration followingsubtraction of blank values.

PDGFRβ Kinase Assay

Biochemical PDGFRβ kinase assays were performed in 96 well microtiterplates that were coated overnight with 75 μg of poly-Glu-Tyr (4:1) in 10mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates werewashed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked byincubation with PBS containing 1% BSA, then washed with 2 mls per wellPBS-T prior to starting the reaction. Reactions were carried out in 100μL reaction volumes containing 36 μM ATP in kinase buffer (50 mM Hepesbuffer pH 7.4, 20 mM MgCl₂, 0.1 mM MnCl₂ and 0.2 mM Na₃VO₄). Testcompounds were reconstituted in 100% DMSO and added to the reaction togive a final DMSO concentration of 5%. Reactions were initiated by theaddition 20 ul per well of kinase buffer containing 200-300 ng purifiedcytoplasmic domain PDGFR-b protein (Millipore). Following a 60 minuteincubation at 30° C., the reactions were washed 2 mls per well PBS-T.100 μl of a monoclonal anti-phosphotyrosine antibody-peroxidaseconjugate diluted 1:10,000 in PBS-T was added to the wells for 30minutes. Following a 2 mls per well wash with PBS-Tween-20, 100 μl of0-Phenylenediamine Dihydrochloride in phosphate-citrate buffer,containing urea hydrogen peroxide, was added to the wells for 7-10minutes as a colorimetric substrate for the peroxidase. The reaction wasterminated by the addition of 100 μl of 2.5N H₂SO₄ to each well and readusing a microplate ELISA reader set at 492 nm. IC₅₀ values for compoundinhibition were calculated directly from graphs of optical density(arbitrary units) versus compound concentration following subtraction ofblank values.

PKR KinaseGlo Assay

Commercially available recombinant human GST-PKR (SignalChem, Canada;1.5 uM-2 uM stock) is diluted to 500 nM in assay buffer (20 mM Tris-HCl,pH 7.2, 10 mM KCl, 10 mM MgCl2, 10% glycerol). Preactivated PKR isdispensed to 384/96-well black plates at 3.125/12.5 uls/well using theliquid handler Janus. Appropriate dilutions of inhibitors are added to384/96-well plate followed by 6.6 uM ATP (final) and incubated for 10minutes at room temperature. The remaining ATP/well is determined byadding 6.25/25 uls/well Kinase-Glo assay mix (Promega) and luminescenceis measured on EnVision luminescence plate reader (integration time, 0.2sec; Perkin-Elmer, Massachusetts, USA). The % inhibition for thecompounds is calculated using ATP only (100% inhibition) and PKR+ATP (0%inhibition). 1050 values are determined by plotting % activity versusinhibitor concentration. Curves are fitted using Activity base XLfit(IDBS, UK) using the formula—

-   -   4 Parameter Logistic Model        fit=(A+((B−A)/(1+(10^((C−x)*D)))))        inv=(C−(log(((B−A)/(y−A))−1)/D))        res=(y−fit)

The biological results for the various compounds are shown below inTable 1.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered orally,subcutaneously, intravenously, intrathecally or some suitablecombination(s) thereof.

In addition to the common dosage forms set out above, the compounds ofthis invention may also be administered by controlled release meansand/or delivery devices such as those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; and5,366,738.

For use where a composition for intravenous administration is employed,a suitable daily dosage range for anti-inflammatory,anti-atherosclerotic or anti-allergic use is from about 0.001 mg toabout 25 mg (preferably from 0.01 mg to about 1 mg) of a compound ofthis invention per kg of body weight per day and for cytoprotective usefrom about 0.1 mg to about 100 mg (preferably from about 1 mg to about100 mg and more preferably from about 1 mg to about 10 mg) of a compoundof this invention per kg of body weight per day. For the treatment ofdiseases of the eye, ophthalmic preparations for ocular administrationcomprising 0.001-1% by weight solutions or suspensions of the compoundsof this invention in an acceptable ophthalmic formulation may be used.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The magnitude of prophylactic or therapeutic dose of a compound of thisinvention will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound and its routeof administration. It will also vary according to the age, weight andresponse of the individual patient. It is understood that a specificdaily dosage amount can simultaneously be both a therapeuticallyeffective amount, e.g., for treatment to slow progression of an existingcondition, and a prophylactically effective amount, e.g., for preventionof condition.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.001 mg to about 500 mg. In oneembodiment, the quantity of active compound in a unit dose ofpreparation is from about 0.01 mg to about 250 mg. In anotherembodiment, the quantity of active compound in a unit dose ofpreparation is from about 0.1 mg to about 100 mg. In another embodiment,the quantity of active compound in a unit dose of preparation is fromabout 1.0 mg to about 100 mg. In another embodiment, the quantity ofactive compound in a unit dose of preparation is from about 1.0 mg toabout 50 mg. In still another embodiment, the quantity of activecompound in a unit dose of preparation is from about 1.0 mg to about 25mg.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.01mg/day to about 2000 mg/day of the compounds of the present invention.In one embodiment, a daily dosage regimen for oral administration isfrom about 1 mg/day to 1000 mg/day. In another embodiment, a dailydosage regimen for oral administration is from about 1 mg/day to 500mg/day. In another embodiment, a daily dosage regimen for oraladministration is from about 100 mg/day to 500 mg/day. In anotherembodiment, a daily dosage regimen for oral administration is from about1 mg/day to 250 mg/day. In another embodiment, a daily dosage regimenfor oral administration is from about 100 mg/day to 250 mg/day. In stillanother embodiment, a daily dosage regimen for oral administration isfrom about 1 mg/day to 100 mg/day. In still another embodiment, a dailydosage regimen for oral administration is from about 50 mg/day to 100mg/day. In a further embodiment, a daily dosage regimen for oraladministration is from about 1 mg/day to 50 mg/day. In anotherembodiment, a daily dosage regimen for oral administration is from about25 mg/day to 50 mg/day. In a further embodiment, a daily dosage regimenfor oral administration is from about 1 mg/day to 25 mg/day. The dailydosage may be administered in a single dosage or can be divided intofrom two to four divided doses.

In one aspect, the present invention provides a kit comprising atherapeutically effective amount of at least one compound of the presentinvention, or a pharmaceutically acceptable salt of said compound and apharmaceutically acceptable carrier, vehicle or diluents, and directionsfor the use of said kit.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in therelevant art and are intended to fall within the scope of the appendedclaims.

TABLE 1 VEGFR2 PDGFRβ PKR Kinase Kinase KinaseGlo Assay Assay AssayStructure IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)

Example 1 4760 na 810

Example 2 >100000 na 89

Example 3 >10000  na 282

Example 4 >100000 na 1934

Example 5 5 17 >40,000

Example 6 443 na >40,000

Example 7 10 244 na

Example 8 16 130 na

Example 9 11 na na

Example 10 274 >10000 na

Example 11 6 239 na

Example 12 5 19 na

Example 13 8 na na

Example 15 1850 na 2820

Example 16 na na 176

Example 17 na na 130

Example 18 na na 749

What is claimed is:
 1. A compound represented by Formula I, itsenantiomers, diastereoisomers, or a pharmaceutically acceptable saltthereof:

wherein: X is N; R¹ is substituted or unsubstituted aromaticheterocycle; R² is hydrogen; R³ is hydrogen; R⁴ is hydrogen or OR⁹; R⁵is OR⁹ or hydrogen; R⁶ is OR⁹ or hydrogen; R⁷ is hydrogen; and R⁹ ishydrogen or substituted or unsubstituted alkyl.
 2. A pharmaceuticalcomposition comprising as active ingredient a therapeutically effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable adjuvant,diluent or carrier.
 3. A compound selected from the group consisting of:6-(pyridin-3-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-phenyl-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;2-anilino-N-pyridin-3-yl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide;6-benzoyl-N-[5-(ethylsulfonyl)-2-methoxyphenyl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(4-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(3-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(2-methoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(3-fluorophenyl)-2-(pyridin-3-ylcarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-amine;6-(3-methyl-2-furoyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;6-[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;6-(2-thienylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;6-isonicotinoyl-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;6-(pyridin-2-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(3,4-dimethoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;N-(3,5-dimethoxyphenyl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;methyl2-[(3,4,5-trimethoxyphenyl)amino]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate;2-[(3,4,5-trimethoxyphenyl)amino]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide;and7-(pyridin-3-ylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-3-amine,or a pharmaceutically acceptable salt thereof.
 4. A compound, selectedfrom:N-(1-methyl-1H-pyrazol-5-yl)-6-(pyridin-3-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;and2-(pyridin-3-ylcarbonyl)-N-3-thienyl-1,2,3,4-tetrahydroisoquinolin-6-amine,or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising as active ingredient a therapeutically effectiveamount of a compound according to claim 4, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable adjuvant,diluent or carrier.